Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of uterine sarcoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Risk factors.
• Prognosis.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information About Uterine Sarcoma

Related Summaries

Other PDQ summaries containing information related to uterine sarcoma include:

• Adult Soft Tissue Sarcoma Treatment.
• Endometrial Cancer Treatment.
• Childhood Soft Tissue Sarcoma Treatment.
• Endometrial Cancer Screening.
• Endometrial Cancer Prevention.

Risk Factors

The only documented etiologic factor in 10% to 25% of these malignancies is prior pelvic radiation therapy, which is often administered for benign uterine bleeding that began 5 to 25 years earlier. An increased incidence of uterine sarcoma has been associated with tamoxifen in the treatment of breast cancer. Subsequently, increases have also been noted when tamoxifen was given to prevent breast cancer in women at increased risk—a possible result of the estrogenic effect of tamoxifen on the uterus. Because of this increase, patients on tamoxifen should have follow-up pelvic examinations and should undergo endometrial biopsy if there is any abnormal uterine bleeding.^[4][5][6]

Prognosis

The prognosis for women with uterine sarcoma is primarily dependent on the extent of disease at the time of diagnosis.^[7] For women with carcinosarcomas, significant predictors of metastatic disease at initial surgery include isthmic or cervical location, lymphatic vascular space invasion, serous and clear cell histology, and grade 2 or 3 carcinoma.^[7] These factors, along with adnexal spread, lymph node metastases, tumor size, peritoneal cytologic findings, and depth of myometrial invasion correlate with progression-free interval.^[7] The presence or absence of stromal heterologous elements, the types of such elements, the grade of the stromal components, and the mitotic activity of the stromal components bear no relationship to the presence or absence of metastases at surgical exploration. However, in one study, women with a well-differentiated sarcomatous component or carcinosarcomas had significantly longer progression-free intervals than those with moderately to poorly differentiated sarcomas for the homologous and heterologous types. The recurrence rate was 44% for homologous tumors and 63% for heterologous tumors. The type of heterologous sarcoma had no effect on the progression-free interval.

For women with leiomyosarcomas, some investigators consider tumor size to be the most important prognostic factor; women with tumors greater than 5.0 cm in maximum diameter have a poor prognosis.^[8] However, in a Gynecologic Oncology Group study, the mitotic index was the only factor significantly related to progression-free interval.^[7] Leiomyosarcomas matched for other known prognostic factors may be more aggressive than their carcinosarcoma counterparts.^[9] The 5-year survival rate for women with stage I disease, which is confined to the corpus, is approximately 50% versus 0% to 20% for the remaining stages.

Cellular Classification of Uterine Sarcoma

The most common histologic types of uterine sarcomas are:
• Carcinosarcomas (mixed mesodermal sarcomas [40%–50%]).
• Leiomyosarcomas (30%).
• Endometrial stromal sarcomas (15%).

The uterine neoplasm classification of the International Society of Gynecologic Pathologists and the World Health Organization uses the term carcinosarcomas for all primary uterine neoplasms containing malignant elements of both epithelial and stromal light microscopic appearances, regardless of whether malignant heterologous elements are present.^[1]

References

Stage Information for Uterine Sarcoma

The FIGO staging for carcinoma of the corpus uteri has been applied to uterine sarcoma.^[1]

Stage I

Stage I sarcoma is confined to the corpus uteri. This stage accounts for 50% of all presentations.

• Stage IA: tumor limited to endometrium.
• Stage IB: invasion to less than 50% of the myometrium.
• Stage IC: invasion to more than 50% of the myometrium.

Stage II

Stage II uterine sarcoma means the cancer has involved the corpus and the cervix but has not extended outside the uterus.

• Stage IIA: endocervical glandular involvement only.
• Stage IIB: cervical stromal invasion.

Stage III

Stage III uterine sarcoma means extension outside of the uterus but confined to the true pelvis.

• Stage IIIA: tumor invades serosa and/or adnexae and/or positive peritoneal cytology.
• Stage IIIB: metastases to pelvic and/or para-aortic lymph nodes.

Stage IV

Stage IV uterine sarcoma means involvement of the bladder or bowel mucosa or metastasis to distant sites.

• Stage IVA: tumor invasion of bladder and/or bowel mucosa.
• Stage IVB: distant metastases, including intra-abdominal and/or inguinal lymph nodes.

Treatment Option Overview

Surgery is often the principal means of diagnosis and is the primary treatment for all patients with uterine sarcoma. If the diagnosis is known, the extent of surgery is planned according to the stage of the tumor. Hysterectomy is usually performed when a uterine malignancy is suspected, except for rare instances when preservation of the uterus in a young patient is deemed safe for the type of cancer (e.g., a totally confined low-grade leiomyosarcoma in a woman who desires to retain childbearing potential). Medically suitable patients with the preoperative diagnosis of uterine sarcoma are considered candidates for abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and periaortic selective lymphadenectomy. Cytologic washings are obtained from the pelvis and abdomen. Thorough examination of the diaphragm, omentum, and upper abdomen is performed.

There is no firm evidence from a prospective study that adjuvant chemotherapy or radiation therapy is of benefit for patients with uterine sarcoma.^[1] In one Gynecologic Oncology Group (GOG) study, the use of adjuvant doxorubicin did not alter the survival rate of patients with resected stage I or stage II uterine sarcomas; however, interpretation of these results is difficult because this study included some patients who received radiation and three types of uterine sarcomas that have variable responses to doxorubicin.^[1][Level of evidence: 1iiA] However, because the risk of disease recurrence is high even with localized presentations, many physicians have considered the use of adjuvant chemotherapy or radiation therapy.^[2] A report of a study (GOG-150) that addressed radiation therapy versus adjuvant chemotherapy is awaited.^[3]

References

Stage I Uterine Sarcoma

Standard treatment options:

1. Surgery (total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and periaortic selective lymphadenectomy).
2. Surgery plus pelvic radiation therapy.
3. Surgery plus adjuvant chemotherapy.
4. Surgery plus adjuvant radiation therapy (EORTC-55874).

In a nonrandomized Gynecologic Oncology Group study in patients with stage I and II carcinosarcomas, those who had pelvic radiation therapy had a significant reduction of recurrences within the radiation treatment field but no alteration in survival.^[1] A large nonrandomized study demonstrated improved survival and a lower local failure rate in patients with mixed mullerian tumors following postoperative external and intracavitary radiation therapy.^[2] One nonrandomized study that predominantly included patients with carcinosarcomas appeared to show benefit for adjuvant therapy with cisplatin and doxorubicin.^[3]

References

Stage II Uterine Sarcoma

Standard treatment options:

1. Surgery (total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and periaortic selective lymphadenectomy).
2. Surgery plus pelvic radiation therapy.
3. Surgery plus adjuvant chemotherapy.
4. Surgery plus adjuvant radiation therapy (EORTC-55874).

In a nonrandomized Gynecologic Oncology Group study in patients with stage I and II carcinosarcomas, those who had pelvic radiation therapy had a significant reduction of recurrences within the radiation treatment field but no alteration in survival.^[1] One nonrandomized study that predominantly included patients with carcinosarcomas appeared to show benefit for adjuvant therapy with cisplatin and doxorubicin.^[2]

References

Stage III Uterine Sarcoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Standard treatment options:

• Surgery (total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and periaortic selective lymphadenectomy, and resection of all gross tumor).

Treatment options under clinical evaluation:

1. Surgery plus pelvic radiation therapy.
2. Surgery plus adjuvant chemotherapy.

Carcinosarcomas (the preferred designation by the World Health Organization [WHO]) are also referred to as mixed mesodermal or mullerian tumors. Controversy exists about the following issues:

• Whether they are true sarcomas.
• Whether the sarcomatous elements are actually derived from a common epithelial cell precursor that also gives rise to the usually more abundant adenocarcinomatous elements.

The stromal components of the carcinosarcomas are further characterized by whether they contain homologous elements (such as malignant mesenchymal tissue considered possibly native to the uterus) or heterologous elements (such as striated muscle, cartilage, or bone, which are foreign to the uterus). Carcinosarcomas parallel endometrial cancer in its postmenopausal predominance and in other of its epidemiologic features; increasingly, the treatment of carcinosarcomas is becoming similar to combined modality approaches for endometrial adenocarcinomas.

Patients who present with uterine sarcoma have been treated on a series of phase II studies (GOG-87B) by the Gynecologic Oncology Group (GOG).^[1][2] These chemotherapy studies have documented some antitumor activity for cisplatin, doxorubicin, and ifosfamide. These studies have also documented differences in response leading to separate trials for patients with carcinosarcomas and leiomyosarcomas. As an example, in patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in patients with carcinosarcomas ^[3] and a 17.2% partial response rate in patients with leiomyosarcomas.^[2]

A randomized comparison (GOG-108) of ifosfamide with or without cisplatin for first-line therapy for patients with measurable advanced or recurrent carcinosarcomas demonstrated a higher response rate (54% vs. 34%) and longer progression-free survival (PFS) on the combination arm (6 months vs. 4 months), but there was no significant improvement in survival (9 months vs. 8 months).^[4][Level of evidence: 1iiA] A follow-up GOG study (GOG-161) utilized 3-day ifosfamide regimens (instead of the more toxic 5-day regimen in the preceding study) for the control and for a combination with paclitaxel (with filgrastim starting on day 4).^[5] The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and overall survival (13.5 months and 8.4 months). The hazard ratio for death favored the combination 0.69 (95% confidence interval, 0.49–0.97).^[5][Level of evidence: 1iiA] In this study, 52% of 179 evaluable patients had recurrent disease, 18% had stage III disease, and 30% had stage IV disease. In addition, imbalances were present in the sites of disease and in the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.

A role for chemotherapy as adjuvant to surgery has not yet been established.

References

Stage IV Uterine Sarcoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

There is currently no standard therapy for patients with stage IV disease. These patients should be entered into an ongoing clinical trial. Information about ongoing clinical trials is available at the NCI Web site.

Carcinosarcomas (the preferred designation by the World Health Organization [WHO]) are also referred to as mixed mesodermal or mullerian tumors. Controversy exists about the following issues:

• Whether they are true sarcomas.
• Whether the sarcomatous elements are actually derived from a common epithelial cell precursor that also gives rise to the usually more abundant adenocarcinomatous elements.

The stromal components of the carcinosarcomas are further characterized by whether they contain homologous elements (such as malignant mesenchymal tissue considered possibly native to the uterus) or heterologous elements (such as striated muscle, cartilage, or bone, which is foreign to the uterus). Carcinosarcomas parallel endometrial cancer in its postmenopausal predominance and in other of its epidemiologic features; increasingly, the treatment of carcinosarcomas is becoming similar to combined modality approaches for endometrial adenocarcinomas.

Patients who present with uterine sarcoma have been treated on a series of phase II studies (GOG-87B) by the Gynecologic Oncology Group (GOG).^[1] These chemotherapy studies have documented some antitumor activity for cisplatin, doxorubicin, and ifosfamide. These studies have also documented differences in response leading to separate trials for patients with carcinosarcomas and leiomyosarcomas. As an example, in patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in patients with carcinosarcomas,^[2] a 33% response rate in patients with endometrial stromal cell sarcomas,^[3], and a 17.2% partial response rate in patients with leiomyosarcomas.^[4] Doxorubicin in combination with dacarbazine or cyclophosphamide is no more active than doxorubicin alone for advanced disease.^[5][6] Cisplatin has activity as first-line therapy and minimal activity as second-line therapy for patients with carcinosarcomas, but cisplatin is inactive as first- or second-line therapy for patients with leiomyosarcomas.^[1][7]

A randomized comparison (GOG-108) of ifosfamide with or without cisplatin for first-line therapy for patients with measurable advanced or recurrent carcinosarcomas demonstrated a higher response rate (54% vs. 34%) and longer progression-free survival (PFS) on the combination arm (6 months vs. 4 months), but there was no significant improvement in survival (9 months vs. 8 months).^[8][Level of evidence: 1iiA] A follow-up GOG study (GOG-161) utilized 3-day ifosfamide regimens (instead of the more toxic 5-day regimen in the preceding study) for the control and for a combination with paclitaxel (with filgrastim starting on day 4).^[9] The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and overall survival (13.5 months and 8.4 months). The hazard ratio for death favored the combination 0.69 (95% confidence interval, 0.49–0.97).^[9][Level of evidence: 1iiA] In this study, 52% of 179 evaluable patients had recurrent disease, 18% had stage III disease, and 30% had stage IV disease. In addition, imbalances were present in the sites of disease and in the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.

References

Recurrent Uterine Sarcoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

There is currently no standard therapy for patients with recurrent disease. These patients should be entered into an ongoing clinical trial. Information about ongoing clinical trials is available at the NCI Web site.

Patients who present with uterine sarcoma have been treated on a series of phase II studies (GOG-87B) by the Gynecologic Oncology Group (GOG). These chemotherapy studies have documented some antitumor activity for cisplatin, doxorubicin, and ifosfamide. These studies have also documented differences in response leading to separate trials for patients with carcinosarcomas and leiomyosarcomas. As an example, in patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in patients with carcinosarcomas,^[1] a 33% response rate in patients with endometrial stromal cell sarcomas,^[2] and a 17.2% partial response rate in patients with leiomyosarcomas.^[3] Doxorubicin in combination with dacarbazine or cyclophosphamide is no more active than doxorubicin alone for recurrent disease.^[4][5] Cisplatin has activity as first-line therapy and minimal activity as second-line therapy for patients with carcinosarcomas, but cisplatin is inactive as first- or second-line therapy for patients with leiomyosarcomas.^[6][7] A regimen of gemcitabine plus docetaxel had a 53% response rate in patients with unresectable leiomyosarcomas and is undergoing further study.^[8]

A randomized comparison (GOG-108) of ifosfamide with or without cisplatin for first-line therapy for patients with measurable advanced or recurrent carcinosarcomas demonstrated a higher response rate (54% vs. 34%) and longer progression-free survival (PFS) on the combination arm (6 months vs. 4 months), but there was no significant improvement in survival (9 months vs. 8 months).^[9][Level of evidence: 1iiA] A follow-up GOG study (GOG-161) utilized 3-day ifosfamide regimens (instead of the more toxic 5-day regimen in the preceding study) for the control and for a combination with paclitaxel (with filgrastim starting on day 4).^[10] The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and overall survival (13.5 months and 8.4 months). The hazard ratio for death favored the combination 0.69 (95% confidence interval, 0.49–0.97).^[10][Level of evidence: 1iiA] In this study, 52% of 179 evaluable patients had recurrent disease, 18% had stage III disease, and 30% had stage IV disease. In addition, imbalances were present in the sites of disease and in the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.

For patients with carcinosarcomas who have localized recurrence to the pelvis confirmed by computed tomographic scanning, radiation therapy may be effective palliation. Phase I and II clinical trials are appropriate for patients who recur with distant metastasis and are unresponsive to first-line phase II trials. High-dose progesterone hormone therapy may be of some benefit to patients with low-grade stromal sarcoma.^[11]

References

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Changes to This Summary (01/11/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Added Purpose of This PDQ Summary as a section and made editorial changes to this summary.